The tumor suppressor activity of IKKalpha in stratified epithelia is exerted in part via the TGF-beta antiproliferative pathway.
The transforming growth factor type beta-1 (TGF-beta) signaling pathway is a major tumor suppressor during early carcinogenesis, and its growth-suppressive activity is commonly lost during early tumor progression. IkappaB kinase alpha (IKKalpha) also acts as a tumor suppressor in stratified epithelia, and its expression and nuclear localization are progressively down-regulated during malignant progression of squamous cell carcinoma (SCC) and acquisition of an invasive phenotype. A critical role for IKKalpha in TGF-beta signaling in stratified epithelia was identified recently during normal keratinocyte differentiation, and both IKKalpha and components of the TGF-beta signaling pathway are required for induction of antiproliferative Myc antagonists in such cells. We now describe that the interaction between IKKalpha and the TGF-beta signaling pathway is also important in a subset of SCCs. In SCCs that are unable to shuttle IKKalpha to the nucleus, defective TGF-beta-induced growth arrest was rescued by introduction of a constitutively nuclear IKKalpha variant. These results suggest that the tumor-suppressive activity of IKKalpha in stratified epithelia may be exerted in part via the TGF-beta signaling pathway.
Marinari
Barbara
B
Departments of Dermatology and Gastroenterology, University of Rome "Tor Vergata", 00133 Rome, Italy.
Moretti
Francesca
F
Botti
Elisabetta
E
Giustizieri
Maria Laura
ML
Descargues
Pascal
P
Giunta
Alessandro
A
Stolfi
Carmine
C
Ballaro
Costanza
C
Papoutsaki
Marina
M
Alemà
Stefano
S
Monteleone
Giovanni
G
Chimenti
Sergio
S
Karin
Michael
M
Costanzo
Antonio
A
D000818:Animals; D002294:Carcinoma, Squamous Cell; D049109:Cell Proliferation; D015536:Down-Regulation; D004848:Epithelium / Q000201:enzymology / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D051550:I-kappa B Kinase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D016271:Proto-Oncogene Proteins c-myc; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D016271:Proto-Oncogene Proteins c-myc; D016212:Transforming Growth Factor beta; D051550:I-kappa B Kinase